How advancing age impacts biological systems responsible for the experience of pain represents a major challenge in the field of pain research. Acknowledging the fact that chronic pain in the elderly is a far more complex condition clinically, biologically, and therapeutically than pain in younger segments of the population underscores the need for integrative studies encompassing behavioral changes and biological mechanisms responsible for alterations in pain perception with advancing age. Over the past 20 years knowledge related to peripheral and central substrates of pain has seen significant advances. Unfortunately, there is little evidence that anything we have learned applies to the pain system in the elderly (animals or humans). An examination of cellular and molecular mechanisms responsible for the development of chronic pain reveals an undeniable overlap with mechanisms responsible for aging, thus providing the rationale for studies evaluating the interaction between the biological process of aging and the pathological condition of chronic pain. Three specific aims related to the impact of advancing age on thermal sensitivity will be addressed, including efforts to define the temporal characteristics of age-related changes in heat and cold sensitivity. Thermal sensitivity will be evaluated with a novel operant-based method of behavioral assessment. Animals will be evaluated longitudinally to study the cumulative effects of age on thermal sensitivity along with the impact of sensory changes on physical performance in male and female Fisher Hybrid (F344BN) rats ranging in age from 8-27 months. Since chronic inflammation is a common condition contributing to musculoskeletal pain, a primary cause of disability in the elderly, efforts will be made to examine the interrelationships among age, chronic inflammation, and changes in autonomic function following inflammatory injury. The predisposing influence of chronic injury early in life to the development of hypersensitivity later in life will also be evaluated. Potential central versus peripheral mechanism(s) for age-dependent changes in sensory function will be evaluated by examining age-dependent changes in spinal microglia and thermal receptor expression in dorsal root ganglia. The proposed research represents: (a) an essential step towards mechanistic studies related to age- dependent molecular and physiological mechanisms of pain;and (b) a pivotal link for translating basic pain research into clinical strategies related to pain disorders in the elderly. To accomplish these objectives a multidisciplinary team consisting of experts in pain and behavior, microglia, physical performance, and statistical analysis will be used to carry out the proposed Research Plan. The proposed studies represent an innovative approach that for the first time combines a longitudinal design with a clinically relevant strategy of operant behavioral assessment to study the effects of age on thermal sensitivity. PUBLIC HEALTH RELEVANCE: Chronic pain in the elderly is a far more complex condition clinically, biologically, and therapeutically than pain in younger segments of the population thus providing the rationale and motivation for studies directed towards understanding the impact of age on the development and maintenance of chronic pain. The proposed research represents: (a) an essential step towards mechanistic studies related to age-dependent behavioral, molecular and physiological mechanisms of pain;and (b) a pivotal link for translating basic pain research into clinical trial strategies related to pain disorders in the elderly.